Apoptosis-inducing Effects Research Articles

New Cytotoxic Sesquiterpene Lactones from the Leaves of Tithonia Diversifolia and their Apoptosis Effect Evaluation in KB Cancer Cells.

From the leaves of Tithonia diversifolia, nine sesquiterpenoids (1-9), including two new ones (tagitinin J (1) and tagitinin K (2)) were isolated and structurally determined. Their chemical structures were elucidated by extensive analyses of the HRESIMS and NMR spectral data, as well as comparison with the literature. All of the isolated compounds (except compounds 7-9) significantly exhibited cytotoxic activity against four human cancer cell lines (KB, HepG2, A549 and MCF7), with IC50 values ranging from 0.29-17.0 μM, which were in the same range as the positive control ellipticine or even lower. Further, the apoptosis induction effects of two new compounds 1 and 2 were also investigated and reported. While compound 2 did not induce the apoptosis in KB cells at test concentrations, compound 1 was found to possess anti-proliferative activity through concentration-dependently inducing cell cycle arrest at S phase, morphological changes, activation of caspase 3, and an increase in the early-stage apoptosis of KB cells at a concentration of 7.26 μM.

A polysaccharide with a triple helix structure from Agaricus bisporus: Characterization and anti-colon cancer activity

In this study, A polysaccharide WAAP-2 (121 kDa) with a triple-helical structure was isolated and purified from Agaricus bisporus for the first time. The physicochemical properties, structural characteristics and anti-colon cancer activity were preliminarily investigated. The primary structure indicated that WAAP-2 was composed of mannose, glucose and galactose and determined the position of the linkage between monosaccharide residues. The advanced structure revealed that WAAP-2 has a triple helix and tangled chain conformation. In the anti-colon cancer activity investigation, WAAP-2 exerted an apoptosis-inducing effect by causing HT-29 cell cycle arrest in S phase. WAAP-2 promoted HT-29 cell apoptosis by up-regulating the expression of Caspase-3 and Bax proteins while down-regulating the expression of Bcl-2 protein. Besides, WAAP-2 could inhibit the migration and invasion of colorectal cancer cells by inducing E-cadherin expression and inhibiting Vimentin expression to affect epithelial mesenchymal transition. This paper is of importance for the application of WAAP-2, a triple-helical structural polysaccharide from Agaricus bisporus, to low-toxicity anti-colon cancer drugs.

Repurposing of Antidiarrheal Loperamide for Treating Melanoma by Inducing Cell Apoptosis and Cell Metastasis Suppression In vitro and In vivo.

Melanoma is the most common skin tumor worldwide and still lacks effective therapeutic agents in clinical practice. Repurposing of existing drugs for clinical tumor treatment is an attractive and effective strategy. Loperamide is a commonly used anti-diarrheal drug with excellent safety profiles. However, the affection and mechanism of loperamide in melanoma remain unknown. Herein, the potential anti-melanoma effects and mechanism of loperamide were investigated in vitro and in vivo. In the present study, we demonstrated that loperamide possessed a strong inhibition in cell viability and proliferation in melanoma using MTT, colony formation and EUD incorporation assays. Meanwhile, xenograft tumor models were established to investigate the anti-melanoma activity of loperamide in vivo. Moreover, the effects of loperamide on apoptosis in melanoma cells and potential mechanisms were explored by Annexin V-FITC apoptosis detection, cell cycle, mitochondrial membrane potential assay, reactive oxygen species level detection, and apoptosis-correlation proteins analysis. Furthermore, loperamide-suppressed melanoma metastasis was studied by migration and invasion assays. What's more, immunohistochemical and immunofluorescence staining assays were applied to demonstrate the mechanism of loperamide against melanoma in vivo. Finally, we performed the analysis of routine blood and blood biochemical, as well as hematoxylin- eosin (H&E) staining, in order to investigate the safety properties of loperamide. Loperamide could observably inhibit melanoma cell proliferation in vitro and in vivo. Meanwhile, loperamide induced melanoma cell apoptosis by accumulation of the sub-G1 cells population, enhancement of reactive oxygen species level, depletion of mitochondrial membrane potential, and apoptosis-related protein activation in vitro. Of note, apoptosis-inducing effects were also observed in vivo. Subsequently, loperamide markedly restrained melanoma cell migration and invasion in vitro and in vivo. Ultimately, loperamide was witnessed to have an amicable safety profile. These findings suggested that repurposing of loperamide might have great potential as a novel and safe alternative strategy to cure melanoma via inhibiting proliferation, inducing apoptosis and cell cycle arrest, and suppressing migration and invasion.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 μM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 μM (MCF-7) and 8.9±0.5 μM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

Oxyresveratrol Enhances the Anti-Cancer Effect of Cisplatin against Epithelial Ovarian Cancer Cells through Suppressing the Activation of Protein Kinase B (AKT).

Epithelial ovarian carcinoma poses a significant challenge due to its resistance to chemotherapy and propensity for metastasis, thereby reducing the effectiveness of conventional treatments. Hence, the identification of novel compounds capable of augmenting the anti-cancer efficacy of platinum-based chemotherapy is imperative. Oxyresveratrol (OXY), a derivative of resveratrol, has been demonstrated to possess antiproliferative and apoptosis-inducing effects across various cancer cell lines. Notably, OXY appears to exert its effects by inhibiting the PI3K/AKT/mTOR signaling pathway. However, the synergistic potential of OXY in combination with cisplatin against epithelial ovarian cancer has not yet been elucidated. The current study investigated the synergistic effects of OXY and cisplatin on the ovarian cancer cell lines SKOV3 and TOV21G. We found that OXY significantly enhanced cisplatin's ability to reduce cell viability, induce apoptosis, induce cell cycle arrest, and increase the proportion of cells in the sub-G1 phase. Furthermore, OXY treatment alone dose-dependently inhibited the production of anti-apoptotic proteins including Mcl-1, Bcl-xL, and XIAP under EGF activation. Mechanistically, OXY suppressed the PI3K/AKT/mTOR signaling pathway by reducing phosphorylated AKT, while having no discernible effect on the MAPK pathway. These findings highlight OXY's potential to enhance ovarian cancer cell sensitivity to chemotherapy, suggesting its development as a pharmaceutical adjunct for clinical use in combination therapies.

Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications.

Hydroxycinnamic acids (HCAs) are plant compounds with anticancer potential due to their antioxidant, anti-inflammatory, apoptosis-inducing, and proliferation-inhibiting effects. This review aims to consolidate and analyze current knowledge on the anticancer effects of HCAs, exploring their mechanisms of action, bioavailability challenges, and potential therapeutic applications. A comprehensive literature search on PubMed/MedLine, Scopus, Web of Science, and Google Scholar focused on the anticancer properties, mechanisms, bioavailability, and safety profiles of HCAs. Studies have shown that HCAs, such as caffeic acid, ferulic acid, and sinapic acid, inhibit the growth of cancer cells in vitro and in vivo and sensitize cancer cells to chemotherapy and radiation therapy. These effects are mediated by mechanisms including the inhibition of cell survival pathways, modulation of gene expression, and induction of oxidative stress and DNA damage. Additionally, several studies have demonstrated that HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to normal cells. However, the toxicity profile of HCAs can vary depending on the specific compound, dosage, and experimental conditions. The anticancer properties of HCAs suggest potential applications in cancer prevention and treatment. However, it is essential to distinguish between their use as dietary supplements and therapeutic agents, as the dosage and formulation suitable for dietary supplements may be insufficient for therapeutic purposes. The regulatory and practical implications of using HCAs in these different contexts require careful consideration. Further research is needed to determine appropriate dosages, formulations, long-term effects, and regulatory frameworks for HCAs as both dietary supplements and therapeutic agents.

Dihydroartemisinin enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis by promoting ROS production

To investigate the effect of dihydroartemisinin (DHA) for enhancing the inhibitory effect of cisplatin (DDP) on DDP-resistant nasopharyngeal carcinoma cell line HNE1/DDP and explore the mechanism. CCK-8 method was used to assess the survival rate of HNE1/DDP cells treated with DHA (0, 5, 10, 20, 40, 80, and 160 μmol/L) and DDP (0, 4, 8, 16, 32, 64, 128 μmol/L) for 24 or 48 h, and the combination index of DHA and DDP was calculated using Compusyn software. HNE1/DDP cells treated with DHA, DDP, or their combination for 24 h were examined for cell viability, proliferation and colony formation ability using CCK-8, EdU and colony-forming assays. Flow cytometry was used to detect cell apoptosis and intracellular reactive oxygen species (ROS). The expression levels of apoptosis-related proteins cleaved PARP, cleaved caspase-9 and cleaved caspase-3 were detected by Western blotting. The effects of N-acetyl-cysteine (a ROS inhibitor) on proliferation and apoptosis of HNE1/DDP cells with combined treatment with DHA and DDP were analyzed. Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 μmol/L) combined with DDP (8, 16, 32, 64, 128 μmol/L) were all below 1. Compared with DHA or DDP alone, their combined treatment more potently decreased the cell viability, colony-forming ability and the number of EdU-positive cells, and significantly increased the apoptotic rate, intracellular ROS level, and the expression levels of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 in HNE1/DDP cells. N-acetyl-cysteine pretreatment obviously attenuated the inhibitory effect on proliferation and apoptosis-inducing effect of DHA combined with DDP in HNE1/DDP cells (P<0.01). DHA enhances the growth-inhibitory and apoptosis-inducing effect of DDP on HNE1/DDP cells possibly by promoting accumulation of intracellular ROS.

EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment

BackgroundBetulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME.MethodsAfter the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models.ResultsWe found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model.ConclusionsEnhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.Graphical abstract

Cynaropicrin, a sesquiterpene lactone, triggers apoptotic cell death in triple negative breast cancer cells.

Breast cancer is the most common cancer in the world. Cynaropicrin is a natural sesquiterpene lactone with potential anticancer effects. The present study was conducted to evaluate the effect of cynaropicrin on proliferation and apoptosis in breast cancer cells. MDA-MB-231 and MCF-7 cell lines were treated with increasing concentrations of cynaropicrin. The viability of both cell lines was measured using MTT assay. Flowcytometry was used to detect apoptotic cells. The expression levels of apoptosis-related genes were determined using quantitative polymerase chain reaction. The protein expression of apoptosis markers was determined by western blotting. Cynaropicrin significantly diminished the proliferation of MDA-MB-231 and MCF-7 cell lines in a dose-dependent manner. Flowcytometry data uncovered that cynaropicrin augmented early and late apoptosis in MDA-MB-231 cells. Real time-PCR and western blotting results also confirmed the upregulation of pro-apoptotic Bax, caspase-3, -8, and 9 as well as downregulated level of anti-apoptotic marker Bcl-2. Cynaropicrin also remarkably increased the activity of caspase-3, -8, and 9 in MDA-MB-231 cells. However, cynaropicrin neither promoted apoptosis in MCF-7 cells nor altered the expression levels and activity of above mentioned apoptotic markers. The present data indicated anti-proliferative properties of cynaropicrin against breast cancer and highlighted apoptosis-inducing effects of this sesquiterpene on triple negative breast cancer (TNBC) cells. These data may suggest cynaropicrin as a potential anti-TNBC agent to tackle therapy resistance in this type of breast cancer.

Octreotide modified liposomes that co-deliver paclitaxel and neferine effectively inhibit ovarian cancer metastasis by specifically binding to the SSTR2 receptors

Early detection of ovarian cancer is challenging, leading to high mortality rates. Paclitaxel has broad-spectrum anti-tumor activity and has been used clinically for the treatment of various cancers. However, the severe side effects of paclitaxel limit its use at high doses. Hence, it is imperative to develop a novel anti-neoplastic agent that can enhance therapeutic efficacy and selectively target tumor sites, thereby mitigating systemic toxicity. In this study, lipid nanoparticles with surface-modified octreotide were constructed by a thin film dispersion method to co-encapsulate paclitaxel and neferine, which are lipophilic compounds, within the phospholipid bilayer, improving their solubility. Liposomes modified with octreotide can increase its active targeting to SKOV3 cells through SSTR-mediated endocytosis and prolong the drug circulation time in vivo. The potential synergistic effects of paclitaxel and neferine were confirmed and quantified by Synergyfinder analysis software. In vitro experimental results showed that neferine can synergistically enhance the cytotoxicity of paclitaxel against human ovarian cancer cells, exerting anti-proliferative, apoptosis-inducing, invasion-suppressing, and angiogenesis-disrupting effects. The in vivo targeting and tumor inhibition of Octreotide-modified liposomes that co-deliver paclitaxel and neferine (OCT-PTX/Nef-Lips) were investigated in mice xenografted with SKOV3 cells. In vivo pharmacodynamic evaluation demonstrated the safe and effective ability of OCT-PTX/Nef-Lips to inhibit tumor volume growth, disrupt tumor tissue morphology, induce apoptosis in tumor cells, and suppress their proliferation. Furthermore, angiogenesis was inhibited through down-regulation of angiogenesis-related proteins (TIE-2, VEGFA, VE-Cadherin, Ang-2).

Computational Study of Lactucine and its Derivatives to Investigate its Anti-cancerous Properties Targeting Apoptosis-inducing Protein

Background: Lactucine is related to the sesquiterpene lactone group of naturally occurring compounds and has a variety of pharmacological effects including anticancer properties found in Chicory, Wormwood, Laurus nobilis, Pyrethrum, Chamomile, etc. Lactucine has an anticancer effect which may induce apoptosis in cancerous cells and protect other cells from getting infected. Objective: In this study, Lactucine and its derivatives were screened, and performed their in silico docking study with the proteins involved in the apoptosis-inducing effect in human leukemia cancer. Methods: The three-dimensional structure of lactucine and its derivatives were retrieved in the SDF format. Active sites of protein structures were determined by Sitemap. LigPrep module was used for geometrical refining of chemical structures of lactucine and its derivatives. The protein preparation wizard of Maestro (Schrodinger) was used for protein preparation. From the receptor-complex structure, the cocrystallized ligands were removed from the active site position of the receptor chain. All ligands were docked using default Glide settings for a grid centered on the ligand and structure. Flexible docking was performed using the extra precision (XP) feature of Glide module. The best docking poses for the lactucine and their derivatives were selected based on their docking score. The ADMET properties of lactucine 15- oxalate have been predicted by admetSAR software. Results: Proteins and ligands three-dimensional structures were retrieved from PDB and Pubchem databases, respectively. All lactucine derivatives suitably docked on the apoptosis-inducing proteins with ample Glide scores Lactucin 15-oxalate interacts with proteins which are responsible for apoptosis with a maximum of six H-bonds. Other types of interactions are also involved, like Pi-cation, Pi-Pi stacking, salt bridges, and halogen bonds. Protein CDK-4 has shown the highest number of H-bond (LYS142 salt bridges), ALA16, VAL14, ASP99, LYS35, TYR17, and ASN145) with the Lactucin 15-oxalate. ADMET properties of lactucin 15-oxalate met with the criteria of being eligible to be a novel drug for the treatment of human leukemia cancer. The Dock score of both the Dasatinib drug and the lactucine-15-oxalate with the apoptosis-inducing protein stipulates that the selected ligand has equitable interaction with the target proteins. Conclusion: In this study, lactucine derivatives were docked with apoptosis-inducing proteins for the prediction of its anticancer effect. Lactucin15-oxalate has shown the highest binding affinity for the CDK-4 target and can be used as a lead compound for cancer treatment. Glide and Dock score for docking of lactucin 15-oxalate with CDK-4, well as the number of hydrogen bonding, is in agreement to use this ligand for study. These in silico results are valuable to proceed with the in vitro and in vivo studies related to the anti-cancer role of lactucin 15-oxalate.

Turmeric and curcumin as adjuncts in controlling Helicobacter pylori-associated diseases: a narrative review.

Non-antibiotic adjuncts may improve Helicobacter pylori infection control. Our aim was to emphasize curcumin benefits in controlling H. pylori infection. We discussed publications in English mostly published since 2020 using keyword search. Curcumin is the main bioactive substance in turmeric. Curcumin inhibited H. pylori growth, urease activity, three cag genes, and biofilms through dose- and strain-dependent activities. Curcumin also displayed numerous anticancer activities such as apoptosis induction, anti-inflammatory and anti-angiogenic effects, caspase-3 upregulation, Bax protein enhancement, p53 gene activation, and chemosensitization. Supplementing triple regimens, the agent increased H. pylori eradication success in three Iranian studies. Bioavailability was improved by liposomal preparations, lipid conjugates, electrospray-encapsulation, and nano-complexation with proteins. The agent was safe at doses of 0.5->4g daily, the most common (in 16% of the users) adverse effect being gastrointestinal upset. Notably, curcumin favorably influences the intestinal microbiota and inhibits Clostridioides difficile. Previous reports showed the inhibitory effect of curcumin on H pylori growth. Curcumin may become an additive in the therapy of H. pylori infection, an adjunct for gastric cancer control, and an agent beneficial to the intestinal microbiota. Further examination is necessary to determine its optimal dosage, synergy with antibiotics, supplementation to various eradication regimens, and prophylactic potential.

Nucleus-targeted carbon dots as peroxidase nanozyme for photoacoustic imaging and phototherapy of tumor

High-purity carbon dots (CDs) with a highly π-conjugated sp2-hybridized graphite structure were prepared by the pulse electrolysis method using the graphite plate as raw material. Photoacoustic signal together with photothermal effect was found in the CDs-dispersed suspensions under near-infrared (NIR) irradiation. For the suspension with the CDs concentration of 500 μg/mL, the photothermal conversion efficiency is high up 64.3% and the solution’s temperature can be increased to 82.2 °C under NIR irradiation. Moreover, CDs can be effectively endocytosed by human hepatoma (HepG2) cells with a few hours, act as peroxidase nanozyme to decompose H2O2 and facilitate the production of reactive oxygen species. Under NIR irradiation, CDs exhibit an outstanding apoptosis-inducing effect on HepG2 cells by the photothermal effect. In addition, in vivo experiments show that CDs can be used in photoacoustic imaging (PAI) and guiding the tumor treatment. As a result, the nucleus-targeted CDs with an unique combination of PAI and photothermal effect have potential in cancer diagnosis and treatment.

Influence of TLR4 signaling on Cannabidiol’s antitumor effectiveness in lung adenocarcinoma cells

Abstract Objectives Lung cancer remains a predominant cancer type with high incidence and low survival rates. Key challenges in its treatment include impaired cellular mechanisms, notably resistance to apoptosis and altered immune responses. A critical aspect in this context is the heightened TLR4-mediated signaling, known to promote cell survival, metastasis, and resistance to cell death, particularly impacting immune microenvironment regulation. This study focuses on evaluating the impact of TLR4 signaling activation on potential therapeutic strategies. Methods Our research utilizes Cannabidiol (CBD), a compound already employed in mitigating chemotherapy side effects in lung adenocarcinoma, recognized for its antitumor properties including antiproliferative, antimetastatic, and apoptosis-inducing effects. However, the effectiveness of CBD in lung cancer cells with elevated TLR4 signaling remains uncertain. Results Our findings reveal that the combination of CBD and TLR4 agonist affects cell viability, proliferation, cell cycle progression, apoptosis, and gene expression related to immune response and extracellular matrix regulation. In lung adenocarcinoma cells with activated TLR4, CBD shows an increased IC50 value, reflecting reduced antiproliferative capacity. Furthermore, its efficacy in arresting the cell cycle and inducing apoptosis is also compromised. The influence on immune response and extracellular matrix regulation is also altered in TLR4-activated cells. Conclusions These results indicate that TLR4 activation significantly diminishes the antitumor efficacy of CBD. This highlights the importance of considering TLR4 signaling activation in future research on therapeutic agents like CBD for cancer treatment.

In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What’s more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

Inhibitory effects of medium-chain fatty acids on the proliferation of human breast cancer cells via suppression of Akt/mTOR pathway and modulating the Bcl-2 family protein.

Medium-chain fatty acids (MCFAs) have 6-12 carbon atoms and are instantly absorbed into the bloodstream before traveling to the portal vein and the liver, where they are immediately used for energy and may have antitumor effects. Its role in breast cancer is poorly understood. To investigate the apoptosis-inducing effect of MCFAs in breast cancer cells, cell viability assay, colony formation assay, cell migration assay, cell invasion assay, nuclear morphology, cell cycle assay, intracellular reactive oxygen species (ROS), matrix metalloproteinase (MMP), apoptosis, RT-qPCR analysis, and Western blot analysis were performed. In the present study, MCFA treatments reduced proliferative capability, increased ROS level, increased the depletion of MMP, induced G0/G1 and S phase cell cycle arrest, and late apoptosis of breast cancer cells in an effective concentration. Besides, MCFA treatment contributed to the upregulation of proapoptotic protein (BAK) and caspase-3, and the downregulation of antiapoptotic protein (Bcl-2). Mechanistically, phosphorylation levels of EGFR, Akt, and mTOR were significantly reduced in breast cancer cells treated with MCFAs. However, no significant changes in apoptosis and signaling-related proteins were observed in lauric acid-treated ER-positive cancer cells. Our findings suggested that MCFAs suppressed breast cancer cell proliferation by modulating the PI3K/Akt/mTOR signaling pathway. MCFAs may be a promising therapeutic drug for treating breast cancer.

Medicinal plants cultivated in Egypt with anticancer potential; a systematic review

AbstractThe increase in cases of various cancers, the number of cancer patients, and the serious side effects of current chemical treatments have encouraged researchers to discover novel and more effective drugs from plant sources. In this review, PubMed and Scopus were searched for English-language peer-reviewed articles published since 1994, using the keywords: Medicinal plants, Egypt, and Cancer. The inclusion criteria for this systematic review were English peer-reviewed original research articles. A total of 286 studies were included. Studies have shown that the active compounds in certain plants can have anticancer activities by various mechanisms, such as cell cycle arrest, apoptosis induction, and antioxidant effects. Additionally, it is evident that medicinal plants can act as inhibitors of cancer cells. Plants can also act as immune checkpoint inhibitors, which inhibit proteins such as PD-L1 on tumor cells, PD-1 and CTLA-4 on T cells, and help to regulate immune responses. This review also discusses the efficacy of nanoparticles of these plants against cancer cells. The findings indicate the high potential of investigating the bioactive anticancer components of Egyptian medicinal plants for advancing novel treatments that are more effective in combating cancer. The extracts and active compounds of the medicinal plants detailed in this review could provide the foundation for further clinical trials to be conducted, to develop new anticancer drugs.

Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation.

Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics. We identified four compounds that bind to the ATP-binding region of the EGFR-TK using AutoDock 4.0 and AutoDock Vina1.1.2 and post-docking investigations. The ligand showed hydrophobic interactions to the hydrophobic region of the binding site and engaged in hydrogen bonding with Met793. The ligands also explored π-cation interactions between the π-system of the ligand-phenyl ring and the positive amino group of Lys745. Molecular mechanics Poisson-Boltzmann surface area MM/PBSA per-residue energy decomposition analyses revealed that Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844 contributed the most to the binding energy. Biological evaluation of the retrieved hit compounds showed suppressing activity against EGFR auto phosphorylation and selective apoptosis-induced effects toward lung cancer cells harboring the EGFR L858R/T790M double mutation. Our work anticipated into novel and specific EGFR-TKIs and identified new compounds with therapeutic potential against lung cancer.

تقييم نشاط التئام الجروح وتحفيز موت الخلايا المبرمج لمشتقات الكينازولينون الجديدة

Background: Chemotherapeutic medication treatment for cancer is typically used in conjunction with other techniques as part of a routine regimen. It is well established that the capacity of different chemotherapeutic drugs to induce apoptosis is correlated with their anticancer efficacy. Quinazolinone-based drugs have demonstrated excellent responses from several cancer cell types. These substances have a lot of potential for use as building blocks in the creation of apoptosis inducers. Objective: To assess the new quinazolinone derivatives (M1 and M2) that were recently synthesized for their potential to halt wound healing and to use the acridine orange/propidium iodide (AO/PI) double stain to assess their capacity to induce apoptosis in the chosen cancer cell lines. Methods: Using the breast carcinoma cell line (MCF-7) and the lung adenocarcinoma cell line (A549), two quinazolinone derivatives (M1 and M2) were investigated for their capacity to inhibit wound healing and induce apoptosis. Results: In both cell lines, the chemicals were found to be effective inducers of apoptosis and to considerably limit wound healing. Conclusions: In cancer cell lines (MCF-7 and A549), compounds M1 and M2 efficiently inhibited wound repair and triggered apoptosis.

Comparative Analysis of CDK4/6 Inhibitors (Ribociclib and Palbociclib) combined with Enzalutamide in Triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is recognized as a challenging subtype due to its poor prognosis. Recent molecular profiling studies have unveiled a significant subset expressing the androgen receptor (AR) subset which may respond to AR-blocking agents, offering a potentially effective treatment strategy. This study aims to investigate the potential synergistic cytotoxic and apoptotic effects of the AR antagonist enzalutamide (ENZA) in combination with CDK4/6 inhibitors palbociclib (PB) or ribociclib (RB) and compare the effectiveness of these combinations in TNBC cells. Results revaled that ENZA in combination with PB or RB induced synergistic cytotoxic cytotoxicity in all tested TNBC cell lines. While synergistic cytotoxic combinations of ENZA with PB did not induce apoptosis in any TNBC cell line, ENZA+RB combinations exhibited a synergistic apoptotic effect. This study suggests that the ENZA+RB combination may be more favorable due to its apoptosis-inducing effect. However, these data need to be further supported by detailed in vivo and clinical studies